6-[D(-)-alpha-amino-phenylacetamido]-penicillanic acids have the formula: ##STR1## wherein R is hydrogen or hydroxy have a broad spectrum of activity against both gram-positive and gram-negative bacteria. Oral administration results in high blood levels. Among the compounds of formula I are amoxicillin and ampicillin.
However, the only dosage forms available for the compounds of formula I are for parenteral or intravenous administration by means of water-soluble salts. These salts in aqueous solutions have a very short half-life.
Various aldehyde and ketone condensation products of alpha-aminopenicillins of formula I are known. For example, derivatives of various alpha-aminopenicillins with nitro-substituted heterocyclic aldehydes are disclosed in U.S. Pat. No. 3,647,781. Other patents and patent publications disclosing derivatives of alpha-aminopenicillins with aldehydes and ketones include U.S. Pat. Nos. 3,198,804 and 3,558,602 (various aldehydes and ketones), U.S. Pat. No. 3,198,788 (formaldehyde), U.S. Pat. No. 3,230,214 (aromatic or heteroaromatic aldehydes containing an ortho hydroxyl substituent), U.S. Pat. No. 3,325,479 (diketones), U.S. Pat. Nos. 3,489,746, 3,549,746, 3,814,800 and U.K. Pat. No. 1,224,619 (acetone), U.S. Pat. No. 3,725,389 (N-substituted-4-piperidones), U.S. Pat. No. 3,888,848 (chloral hydrate), DOS 2,258,994 (various aldehydes including acetaldehyde) and South African Pat. No. 72/8474 (acetaldehyde).
These condensation products of the alpha-aminopenicillins of formula I with aldehydes or ketones result in the formation of either an imidazolidinyl compound or a Schiff base or mixtures thereof. These condensation products are readily soluble in water and more stable than the corresponding salts. They are, in fact, bioprecursors of the corresponding alpha-aminopenicillin since they are readily converted in vivo to the corresponding alpha-aminopenicillins. However, the in vivo liberation of the ketone or aldehyde can cause adverse and/or toxic side effects.
It is, therefore, an object of this invention to prepare new water-soluble forms of alpha-aminopenicillins for oral and parenteral administration, which are stable in aqueous systems and do not have the deleterious side effects as seen for ketone and aldehyde adducts.